Chronic migraine is a debilitating primary headache disorder associated with high personal, familial, and social impact. The diagnosis is made when there are at least 15 headache days monthly including 8 migraine days per month for at least 3 months. The prevalence is 1.4–2.2% in the population. Among individuals diagnosed with chronic migraine, there may be significant variability in headache days with a potential to remit, remain unchanged, or progress to even greater disability. Most chronic migraine progresses from episodic migraine, with several identified risk factors for chronic migraine and migraine progression. The exact mechanism of chronic migraine is unknown but is associated with an increased cortical excitability, central sensitization, alternations in nociceptive signaling, as well as physiological, structural, and functional brain changes. There is evidence for both nonpharmacological and pharmacological treatment options to restore function. The best currently established pharmacologic evidence for the treatment of chronic migraine is onabotulinumtoxinA and topiramate. Behavioral treatments may improve headache symptoms and comorbidities. Emerging data shows potential benefit for neurostimulation, and large well-designed studies are needed. Multicenter randomized placebo-controlled studies of monoclonal antibodies to the calcitonin gene-related peptide, or its receptor, have demonstrated efficacy, tolerability, and safety. Biomarkers are needed to guide prognosis, treatment response, and clinical trials. The concept and management of refractory chronic migraine is discussed, and clinically meaningful endpoints are reviewed.

Purpose of review

Migraine causes more years of life lived with disability than almost any other condition in the world and can significantly impact the lives of individuals with migraine, their families, and society. The use of medication for the prevention of migraine is an integral component to reducing disability caused by migraine. There are many different drug classes that have been investigated and shown efficacy in migraine prophylaxis. This article examines several of the classes of medications that are used for migraine preventive treatment, specifically, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, serotonin antagonists, alpha-adrenergic agonists, and N-methyl-d-aspartic acid receptor antagonists.

Recent findings

There have been randomized control trials investigating medications in these drug classes since the most recent guidelines for migraine prevention in adults were published by the American Academy of Neurology, American Headache Society, and the Canadian Headache Society. In these investigations, enalapril, candesartan, and memantine all demonstrated efficacy for migraine prevention. The evidence for these and the aforementioned drug classes are reviewed.

Summary

When oral medications are being selected for migraine prevention, comorbid and coexistent medical conditions, concomitant medications, patient preference, and pregnancy and breast-feeding plans should be considered. Within the drug classes discussed, memantine and candesartan have a moderate level of evidence for efficacy.

Migraine aura consists of fully reversible focal neurologic symptoms that may precede or coexist with headache in a significant minority of migraine patients. Typical aura symptoms include visual, sensory, and language disturbances. The most recent International Classification of Headache Disorders, 3rd edition (beta version) has added other aura types such as brainstem localizing symptoms, lateralizing weakness, and monocular visual loss. Currently available data from animal models and functional neuroimaging in humans implicate cortical spreading depression (CSD) as the phenomenon underlying migraine aura. Ongoing study suggests that susceptibility to migraine aura and CSD may be genetically mediated. CSD appears to be a potential target for future development of migraine-specific preventive therapies.

Around 10 % of the global adult population has active migraine. The public health burden of migraine is high because migraine attacks are associated with temporary disability and substantial impairment in activities. As such, migraine is ranked as one of the most disabling conditions. The widespread disability produced by migraine is therefore an important target for treatment.

The hallmark of migraine is the head pain, but a plethora of other clinical symptoms is needed for a headache to be qualified as a migraine according to the current diagnostic criteria.

There has been tremendous progress in our acceptance, understanding and treatment possibilities of migraine, but to optimize migraine management, it is important that we continue to improve our understanding of the basic migraine mechanisms. An understanding of migraine pathophysiology must encompass the varied clinical symptoms and relate these findings to anatomy and physiology.

Triptans revolutionized medical recognition and the acute treatment of migraine. Yet, throughout a lifetime, millions of patients who live with migraine endure hundreds of days of disability due to their disease. Most migraine attacks respond to migraine-specific interventions, but attack response does not predict patient response. Generally, migraine patients respond to acute treatment for some, but not necessarily all, attacks of migraine. Consequently, there remains a substantial unmet clinical need for better acute treatment of migraine.

Numerous avenues of research and clinical observation provide insight into potential advances in acute treatment of migraine. These include better delivery systems for existing drugs, as well as the development of potential new therapeutic agents. In addition, new changes in migraine taxonomy and clinical observations of migraine suggest additional important therapeutic opportunities. Based on clinical observations, this article explores future acute treatment needs, drugs in development for acute migraine, and new products that deliver established drugs to improve treatment response.

The headache research field is privileged to have in its preclinical laboratories well-established animal models that significantly facilitate and improve our understanding of headache mechanisms, in particular in terms of the molecular signalling and brain networks involved. A variety of pharmacological screening approaches for novel therapeutics and for the improvement of advanced pharmacological agents can be achieved in translational research utilising these models. The available migraine models have been developed based on our understanding of migraine from clinical, migraine patient-specific evidence. These clinical phenotypes have been successfully employed to model features of the disease physiology in animals and to provide reproducible meaningful physiological measures in the laboratory.

Cognitive dysfunction has recently gained attention as a significant problem among migraine sufferers. All of the clinical studies show poor cognitive performance during migraine attacks, though, the interictal data are conflicting. Migraineurs show impaired cognitive function interictally in most of the clinic-based studies. Population-based studies did not reveal a difference in cognitive functions between migraineurs and controls. The specific cognitive domains involved are information processing speed, basic attention, executive functions, verbal and non-verbal memory and verbal skills. Neurophysiological, imaging and pharmacological studies support clinical symptoms of cognitive impairment in migraine. Longitudinal studies do not suggest progressive cognitive decline over time in migraine patients. Preventive medications and comorbid disorders such as depression and anxiety can impact cognitive function, but cannot fully explain the cognitive impairment in migraine. In contrast to migraine, tension type or cluster headache are not associated with cognitive impairment, at least during headache-free periods.

Chronic migraine (CM) has complex pathophysiology that cannot be easily studied in humans. Therefore, animal models are ideally suited for this type of investigation and have played crucial roles in our understanding of CM pathophysiology and aid in treatment. Multidisciplinary approaches used in animal models explore anatomical circuits, phenotypic traits, electrophysiological activities, biochemical pathways, and genetic manipulations. Examination of pathophysiology, therapeutic and prophylactic treatment options, drug effects, and non-pharmacological therapies is explored in preclinical settings and helps improve their applications in clinical practice. On the other hand, known CM therapies also benefit from animal models when unraveling drug mechanisms, sensitivity, and toxicity. Thus, even with known limitations, animal models are unraveling CM mechanisms and contributing to the development of therapeutic tools with translational implications that will guide personalized therapies.

Among all chronic daily headache (CDH) disorders, chronic migraine (CM) and chronic tension-type headache (CTTH) contribute to most cases of CDH, followed by new daily persistent headache (NDPH), medication oversue headache (MOH), and hemicrania continua. The most studied CDH type in animal models is CM. We will focus on animal models of CM in this chapter.

Migraine, particularly migraine with aura has been associated with an increased risk of vascular events including ischemic and hemorrhagic stroke, myocardial infarction, and angina. Data also indicated that migraineurs, as compared to non-migraineurs, have an increased burden of infarct-like lesions and white matter abnormalities at brain magnetic resonance. There are no tools to identify the migraineurs who will suffer vascular events. Recent onset of the migraine, active migraine, and frequent attacks are features associated with the increased stroke risk; combined oral contraceptives and cigarette smoking may further increase the risk of ischemic stroke in migraineurs. The mechanisms underlying this increased vascular risk are still unclear but experimental studies indicated an increased cellular excitability in migraineurs that may make the brain tissue more susceptible to ischemia. Additionally, clinical data supported an impairment of the vascular function in migraineurs at the systemic level. There is currently no direct evidence to support that a migraine prophylactic treatment can reduce future stroke risk; however, we cannot exclude that migraine prophylaxis, by raising the threshold for spreading depolarization, may lower stroke risk.

Purpose of Review

A wide variety of triggers prompt attacks in episodic migraine. Although experimental triggers such as glyceryl trinitrate reliably produce migraine, natural triggers are much less predictable and vary in importance between individuals. This review describes the most common triggers in episodic migraine and provides strategies for managing them in clinical practice.

Recent Findings

Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned. Clinical studies have verified that fasting, premenstrual periods in women, “letdown” after stress, and most likely low barometric pressures are migraine triggers. Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers.

Summary

Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment. Many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. Healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time.